DESCRIPTION: (Applicant's Description) African American and Caucasian populations in the United States manifest distinctly different profiles of tobacco-related neoplasms. Analyses of smoking patterns by these groups have not revealed a higher intake of cigarettes per day to account for the observed higher prevalence of aerodigestive cancer among African Americans, or differences in type of tobacco products preferred, which might help explain the observed lower rates of urinary bladder cancer among blacks. The current proposal is a continuation and extension of our metabolic epidemiological study designed to elucidate whether differences in metabolic capacity resulting in differences in exposure of individuals and target tissues to activated tobacco smoke carcinogens are responsible for the observed variations in site-specific cancer incidence. The proposed five-year investigation will consist of four major studies. In Study A, a total of 320 healthy smokers, 80 of each race-sex combination will be recruited. In this community-based cross-sectional study, questionnaire data on lifestyle, smoking history and diet will be obtained. In addition, several new biomarkers for exposure and susceptibility to tobacco-smoke carcinogens will be studied including 4-aminobiphenyl hemoglobin adducts, NNK and PAH urinary metabolites, and genetic polymorphisms in genes coding for enzymes involved in tobacco-smoke carcinogen metabolism including GSTM1, CYP1A1 and CYP2E1, and the DNA repair enzyme, O6-alkylguanine-DNA alkyltransferase (AGT-1). In Study B, the relationship between NNAL-glucuronidation phenotype, PAH exposure and metabolism biomarkers and risk for lung cancer will be investigated in 140 cases and matched controls. In Study C, a larger-scale case-control study (1175 subjects per group), the relationship between carcinogen metabolism and DNA repair genotypes and lung cancer risk will be examined. Finally, in Study D, the association of acetylation genotype and other selected biomarkers of bladder cancer risk will be investigated in African Americans and Caucasians using a case-control design with 140 subjects per group. Overall, this project attempts to provide mechanisms whereby differences in site-specific cancer incidence between the races are elucidated and draws upon the results from Projects 2 and 4 of this integrated program and the American Health Foundation's large data base of tobacco-related cancers. The unique approach in metabolic epidemiology, combining appropriate questionnaire data with laboratory results obtained from diverse populations, will enable us to more fully understand the observed diversity in cancer prevalence.